Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Chronic liver damage caused by chronic intake of alcohol and hepatitis viral infections is a major risk factor for HCC pathogenesis. In particular, there is compelling evidence that alcohol consumption and HCV infection synergistically induce liver damage, which culminates in an increased incidence of HCC. Molecular analyses and animal modeling have demonstrated that alcohol, with or without HCV infection, is not sufficient to induce HCC in vivo. It is believed that alcoholic liver disease (ALD), especially when accompanied by HCV infection, provides an environment that predisposes to HCC development. However, additional genetic mutations are required to transform the hepatocytes into malignant cells and induce liver tumor formation. In the present application, we hypothesize that certain genetic events, such as c-Myc or c-Met overexpression will lead to HCC formation in chronic alcohol fed mice and/or alcohol fed HCV Ns5a Transgenic (Ns5aTg) mice. In addition, we also hypothesize that chronic alcohol feeding will accelerate tumor growth induced by combination of oncogenes. To test these hypotheses, we propose the following two aims. In Aim One, we will determine whether c-Myc or c-Met overexpression leads to hepatic carcinogenesis in chronic alcohol fed wildtype mice or chronic alcohol fed HCV Ns5aTg mice. And in Aim Two, we will determine whether chronic alcohol feeding accelerates liver tumor growth induced by c-Met/CCND1 or c-Met/Spry2Y55F. Once we are able to establish HCC tumor models for ALD or ALD/HCV mice, we will further characterize the molecular, genetic and biochemical features as well as epigenetic modifications in the tumor tissues. Altogether, the proposed studies will assist to identify important driver oncogenes that have critical roles during liver cancer pathogenesis, and provide novel insight into the molecular mechanisms of HCC development in the context of alcohol induced liver injury. The novel mouse models established in the study will be of great usefulness to further characterize therapeutic interventions to prevent or treat hepatic carcinogenesis in patients with ALD. PUBLIC HEALTH RELEVANCE: Liver cancer is a deadly disease, and chronic alcohol intake is a major risk factor in liver cancer development. In this application, we propose to apply an innovative technology to identify genes that promote liver cancer development in alcoholic liver disease models. The results will likely to lead to better prevention and/or treatment strategies for alcohol induce liver cancer.